IVIg for apparently autoimmune small-fiber polyneuropathy ...

In press version of 11-5-17

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Therapeutic Advances in Neurological Disorders TAN-17-OR-0015 in press

IVIg for apparently autoimmune small-fiber polyneuropathy: First analysis of efficacy and safety

Xiaolei Liu MD*?, Roi Treister PhD*, Magdalena Lang MD*, Anne Louise Oaklander MD, PhD*#

* Department of Neurology, Massachusetts General Hospital, Harvard Medical School, USA ? Department of Neurology, Dayi Hospital of Shanxi Medical University, China # Departments of Pathology (Neuropathology), Massachusetts General Hospital, Harvard

Medical School, USA

Corresponding Author: Anne Louise Oaklander, M.D., Ph.D. Massachusetts General Hospital 275 Charles Street/Warren Bldg. 310 Boston, MA 02114. Tel: 617-726-9391 Fax: 617-726-0473 E-mail: aloaklander@mgh.harvard.edu Email addresses for all coauthors Xiaolei Liu liuxiaolei7760@ Roi Treister treister.roi@ Magdalena Lang magdalena.lang@

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Abstract Objectives Small-fiber polyneuropathy (SFPN) has various underlying causes, including associations with systemic autoimmune conditions. We have proposed a new cause; small-fiber-targeting autoimmune diseases akin to Guillain-Barr? and chronic inflammatory demyelinating polyneuropathy (CIDP). There are no treatment studies yet for this "apparently autoimmune SFPN" (aaSFPN), but intravenous immunoglobulin (IVIg), first-line for Guillain-Barr? and CIDP, is prescribed off-label for aaSFPN despite very high cost. This project aimed to conduct the first systematic evaluation of IVIg's effectiveness for aaSFPN. Methods With IRB approval, we extracted all available paper and electronic medical records of qualifying patients. Inclusion required having objectively confirmed SFPN, autoimmune attribution, and other potential causes excluded. IVIg needed to have been dosed at 1gram/kg/4 weeks for 3 months. We chose two primary outcomes?changes in composite autonomic function testing (AFT) reports of SFPN and in pain severity?to capture objective as well as patient-prioritized outcomes. Results Among all 55 eligible patients, SFPN had been confirmed by 3/3 nerve biopsies, 62% of skin biopsies, and 89% of composite autonomic function testing (AFT). Evidence of autoimmunity included 27% of patients having systemic autoimmune disorders, 20% having prior organ-specific autoimmune illnesses, and 80% having 1/5 abnormal blood-test markers of autoimmunity. 73% had apparent small-fiber-restricted autoimmunity. IVIg treatment duration averaged 28 ? 25 months. The proportion of AFTs interpreted as indicating SFPN dropped from 89% at baseline to 55% (p0.001). Sweat production normalized (p=0.039) and all the other 4 domains trended towards improvement. Among patients with pre-treatment pain 3/10, severity averaging 6.3?1.7 dropped to 5.2?2.1 (p=0.007). 74% of patients rated themselves "improved" and their neurologists labeled 77% as "IVIg responders". 16% entered remissions that were sustained after IVIg withdrawal. All adverse events were expected; most were typical infusion reactions. The two moderate complications (3.6%) were vein thromboses not requiring discontinuation. The one severe event (1.8%), hemolytic anemia, remitted after IVIg discontinuation. Conclusion These results provide Class IV, real-world, proof-of-concept evidence suggesting that IVIg is safe and effective for rigorously selected SFPN patients with apparent autoimmune causality. They provide rationale for prospective trials, inform about trial design, and indirectly support the discovery of small-fiber-targeted autoimmune illnesses.

Keywords Peripheral nervous system diseases, Intravenous immunoglobulin, Neuropathic pain, Dysautonomia, Autoimmune diseases, Immunotherapy

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Introduction The polyneuropathies involve widespread damage to the body's peripheral nerves. "Small-fiber polyneuropathy" (SFPN), also known as small-fiber neuropathy, refers to those polyneuropathies that preferentially affect peripheral neurons with the thinnest axons, including the unmyelinated C-fibers, thinly myelinated A- somatosensory axons, and the sympathetic and parasympathetic neurons. In the past, these were dichotomized as somatic versus autonomic, but immunohistochemical studies blurred the distinction, revealing non-sensory functions of "somatosensory" axons including innervation and control of sweating, the small blood vessels, and bone.1, 2 Plus careful evaluation showed that most patients with somatosensory complaints such as neuropathic pain, itch, or sensory loss also have autonomic involvement,3 hence the tem "small fiber polyneuropathy". Applying the only population-based estimate of its prevalence, 52.95/100,0004 yields an estimated 2017 global prevalence approaching 4 million. This is an underestimate, since it required neurologists' confirmation, whereas most patients remain undiagnosed. Given recent reports that SFPN underlies 40% of the fibromyalgia syndrome5, 6 there could be 400 million cases worldwide.

Small-fiber neurons multifunctionality explains why SFPN increases risk of multiple symptoms. The most common are chronic widespread pain and/or itch,7 postural hypotension and/or tachycardia (POTS),8 nausea, constipation and/or diarrhea, disordered sweating, followed by urological and sexual dysfunction. Recent studies suggest that SFPN is also associated with symptoms traditionally thought to originate in the brain, including chronic headaches and cognitive concerns.9, 10 SFPN can even cause abnormal brain blood flow and functional connectivity that might contribute to the "brain fog" some patients report.11

Given these many symptoms, it can be ineffective to treat only with symptom palliation. The polypharmacy that often ensues is expensive and can cause side effects. The use of opioids to manage chronic pain has been particularly problematic. Identifying and remediating the specific medical cause in each patient is a better strategy. Small-fiber axons grow throughout life, so curtailing ongoing damage can permit them to regenerate to their varied targets. One treatment can improve and sometimes resolve multiple symptoms and restore dysfunctions.

Because small-fiber axons are long and thin, they are vulnerable to disruptions in axon maintenance by any medical problem, including more than a dozen medical causes.12 Diabetes, the most common cause in developed countries, is estimated to cause half of small-fiber predominant neuropathy.13 The 2nd largest group of SFPN patients, estimated at 20-50%,4, 14-17 comprises patients with no apparent cause at first evaluation; so-called "cryptogenic" or "initially idiopathic" (iiSFPN). Ameliorating or curing diabetes mitigates complications including neuropathy18 as do disease-modifying treatments for nutritional, toxic, and infectious causes, but there are no options for the 30-50% of patients with iiSFPN.

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We and others have suggested that autoimmunity plays a far greater role in iiSFPN than recognized. Systemic autoimmune conditions linked to SFPN include lupus, rheumatoid arthritis, sarcoidosis, vasculitis, and celiac.19-35 Sj?gren's is the most common among these,36-38 but virtually nothing is known about how systemic autoimmune diseases affect small-fibers.

We have proposed a new cause of iiSFPN?autoimmunity specifically targeting small-fiber epitopes. Given the current lack of proof, we call this "apparently autoimmune" SFPN (aaSFPN). This concept is biologically plausible, akin to the well-characterized acute and chronic large-fiber-targeting autoimmune diseases Guillain-Barr? syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), and multifocal motor mononeuropathy (MMN).39, 40 The current very limited evidence about mechanisms suggests that autoantibodies and complement consumption3, 12 are more important than cytotoxic T-cell attack. This discovery has important implications for medical care, given the prevalence and disability of SFPN disability, and the widespread availability and proven efficacy of old and new immunotherapies for autoimmune neuropathies.

The concept of aaSFPN began with reports of a few iiSFPN patients who responded to treatment with corticosteroids or pooled human intravenous immunoglobulins (IVIg).41-44 The first case series found corticosteroids efficacious in 10/15 SFPN patients (67%) with improvement in symptoms plus objective tests.3 Since prolonged corticosteroids can cause complications, IVIg is increasingly prescribed off-label for aaSFPN. It is a first-line treatment for GBS, CIDP, and MMN45-48 that modifies B- and T-cells, inhibits antibody production and interferes with the complement cascade. Most nerve specialists know how to manage IVIg, and dosing parameters were established in trials such as the Immune Globulin Intravenous CIDP Efficacy (ICE) trial, a large double-blind, placebo-controlled, randomized crossover trial.49 In addition to confirming efficacy, these trials established the safety outcomes and dosing algorithms we applied here.50, 51

All of the earlier small series document favorable outcomes from IVIg treatment of SFPN, for instance in 3 patients with associated celiac,52 3 with sarcoidosis,53 and 6 with Sj?gren's syndrome.54, 55 In our case series of early-onset SFPN, 5/8 (62%) improved clinically with early evidence of improved skin biopsies and AFT.3 A multicenter, double-blind trial of IVIg in 23 patients with eosinophilic granulomatosis with polyangiitis (Churg-Strauss) reported efficacy for pain, a secondary outcome.56

However, supplies are limited, administration is difficult, and yearly cost can exceed $100,000, so insurers do not usually pay for IVIg treatment of SFPN. Plus IVIg often causes infusion reactions and rarely causes serious adverse events.57 Systematic studies are needed, and the first randomized, double-blind, placebo-controlled, clinical trial of IVIg for idiopathic small fiber neuropathy has begun recruitment in Europe.58 However, interim data are urgently needed now to guide clinical practice and reimbursement decisions.

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To gain insights from currently available data, we performed structured abstraction from medical records to generate the first large case series for analysis. We chose change in pain severity as a primary outcome because chronic pain is arguably the most disabling symptom of SFPN and one of great concern to patients. Plus, validated patient-reported pain scores were routinely collected.59 However, pain is a subjective patient-reported outcome that is highly susceptible to placebo effects, so we judged it prudent to include an objective outcome that could not be influenced by patient expectations. The strongest candidates were PGP9.5-immunolabeled skin biopsies from the lower leg and composite autonomic function testing (AFT), which have been endorsed for diagnosing SFPN by major neurological societies.60, 61 We selected AFT given the high prevalence of potentially dysautonomic symptoms in SFPN, recommendations to measure autonomic as well as somatic dysfunction when assessing small-fiber neuropathies,62 and prior use of AFT in assessing systemic autoimmune SFPN.31 For secondary outcomes, we extracted all safety data, demographic data, relevant blood-test results, plus patients' and physicians' impressions of change, all generally reported in treatment trials. Insofar as we know, this is the first systematic study of IVIg treatment for "idiopathic" SFPN.

Methods Standard Protocol Approvals, Registrations, and Patient Consents All protocols were approved by the hospital's institutional review board, which waived informed consent.

Study design, case definitions, and baseline patient characteristics Since there are no consensus case definitions, to identify potential subjects, we screened the records of every patient evaluated for SFPN in our hospital-based peripheral-nerve practice since our index case42 through 12/31/15 and developed rigorous research-oriented preliminary case definitions for SFPN, for iiSFPN, and for aaSFPN.

Inclusion required meeting our case definition of "definite SFPN", which required physician's clinical diagnosis plus objective confirmation of diagnosis by distal-leg PGP9.5 -immunolabeled skin biopsy, surgical nerve biopsy, or AFT. Since these studies had been performed in diverse facilities, to add rigor we accepted only original reports and interpretations from JC-accredited clinical labs using standard approved methods and analyses. Skin biopsy diagnosis required density of epidermal nerve fibers 5th centile of predicted.60, 61 For nerve biopsies, diagnosis requires qualitative or morphometric evidence of reduced unmyelinated and/or thinly myelinated axons, prior axonal degeneration in the form of empty Schwann cell stacks, collagen pockets, and sometimes, excess inflammatory cells and clusters of regenerating axons.43, 60, 63, 64 Diagnosis by composite AFT requires appropriate abnormalities in 2/4 domains; heart rate variability during deep breathing (HRDB), heart and

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blood-pressure responses to Valsalva maneuver and tilt, and quantitative sudomotor axon reflex testing (QSART).60, 65

For inclusion, patients also had to meet the case definition of apparently autoimmune SFPN (aaSFPN) we developed. In addition to definite SFPN, this required systematic exclusion of non-immune causes by medical history, exam, and results of recommended blood tests.12 We routinely evaluated for diabetes, prediabetes, thyroid disorders, abnormal vitamin levels, Sj?gren's, celiac, hepatitis, Lyme disease, and monoclonal gammopathies plus less-common potential causes suggested by individual histories or examinations. Then it required objective evidence of dysimmunity.

We currently recognize two types of aaSFPN, that associated with systemic autoimmunity (either a recognized systemic condition, or evidence of more than one organ-specific condition), and autoimmunity apparently restricted to small-fibers. For patients to be classified with systemic rheumatologic disorders, we preferred a rheumatologist's consultation. For diagnoses of organ-specific autoimmune disorder (e.g. Hashimoto's thyroiditis), we preferred diagnoses made by a primary care providers or appropriate subspecialists using accepted clinical criteria. The MGH case definition of "systemic aaSFPN" thus required having no other apparent cause of neuropathy, plus either a systemic rheumatologic disorder, or autoimmune disease affecting at least one other organ system.

Classification of a patient as having nerve-specific aaSFPN was more speculative and rheumatologists were often consulted. This case definition also required no other apparent cause of neuropathy, no systemic rheumatologic diagnosis, plus objective supporting evidence including inflammatory infiltrates within nerve or skin biopsies. Persistent, otherwise unexplained, blood-test markers of dysimmunity/inflammation were also accepted. These comprised antinuclear antibodies (ANA, conservatively defined as 1:160 dilution), elevated erythrocyte sedimentation rate (ESR; 15 mm/h), low complement component 4 (C4; < 20 mg/dl), low complement component 3 (C3; ................
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